Iron is the most abundant transition metal essential for numerous cellular processes. Although most mammalian cells acquire iron through transferrin receptors, molecular players of iron utilization under iron restriction are incompletely understood. To address this, we performed metabolism-focused CRISPRa gain-of-function screens, which revealed metabolic limitations under stress conditions. Iron restriction screens identified not only expected members of iron utilization pathways but also SLCO2B1, a poorly characterized membrane carrier. SLCO2B1 expression is sufficient to increase intracellular iron, bypass the essentiality of the transferrin receptor, and enable proliferation under iron restriction. Mechanistically, SLCO2B1 mediates heme analog import in cellular assays. Heme uptake by SLCO2B1 provides sufficient iron for proliferation through heme oxygenases. Notably, SLCO2B1 is predominantly expressed in microglia in the brain, and primary Slco2b1^−/− mouse microglia exhibit strong defects in heme analog import. Altogether, our work identifies SLCO2B1 as a microglia-enriched plasma membrane heme importer and provides a genetic platform to identify metabolic limitations under stress conditions.

铁是众多细胞过程所必需的最丰富的过渡金属。尽管大多数哺乳动物细胞通过转铁蛋白受体获取铁，但铁限制下铁利用的分子参与者尚不完全清楚。为了解决这个问题，我们进行了以代谢为重点的 CRISPRa 功能获得筛选，揭示了应激条件下的代谢限制。铁限制筛选不仅鉴定了铁利用途径的预期成员，还鉴定了SLCO2B1（一种特征较差的膜载体）。 SLCO2B1表达足以增加细胞内铁，绕过转铁蛋白受体的必要性，并在铁限制下实现增殖。从机制上讲，SLCO2B1 介导细胞测定中血红素类似物的输入。 SLCO2B1 摄取的血红素通过血红素加氧酶为增殖提供足够的铁。值得注意的是， SLCO2B1主要在大脑中的小胶质细胞中表达，而原代Slco2b1 ^−/−小鼠小胶质细胞在血红素类似物输入方面表现出强烈的缺陷。总而言之，我们的工作将 SLCO2B1 确定为富含小胶质细胞的质膜血红素输入者，并提供了一个遗传平台来识别应激条件下的代谢限制。